Type 1 diabetes (T1D) is a disorder that arises following the autoimmune destruction of insulin producing pancreatic cells. Previous studies, including many emanating from this P01 in previous years, have demonstrated that individuals with T1D display a number of immunological abnormalities (e.g., frequency and function of iNKT cells, maturation of dendritic cells, interactions between regulatory and effector T cells, cytokin production, etc.). However, the contribution of specific genes to this process as well as an informative description of the interactions between specialized cells and molecules of the innate and adaptive immune systems that lead to a loss of tolerance to cells and eventually T1D remains unclear. Thus, our goal in seeking renewal of this P01 is to elucidate the mechanisms by which genes; IFIH1,TYK2 (investigated in Project 1) and IL18RAP, TLR8 (Project 2) impart immunoregulatory abnormalities that result in aberrant iNKT development, inflammatory antigen presenting cells, expansion of autoreactive lymphocytes, and defective regulatory/effector mechanisms in T cells. These activities will collectively test our overall hypothesis that defects n these systems are key to engender the autoimmune destruction of pancreatic ? cells that result in T1D. Indeed, this P01 will examine this hypothesis through two separate but highly interactive Projects that share data, use innovative technologies, and assess samples from extremely valuable human subjects with or at various levels of risk for T1D. This latter notion includes analysis of tissue samples from the Network for Pancreatic Organ Donors with Diabetes (nPOD), a heretofore effort unseen in research within the T1D community (i.e., availability of high quality pancreatic and lymphoid tissues from humans). These Projects will be supported by two Core facilities: Core A - Administrative Core; Core B - Biorepository, Immunology and Pathology Core. If successful, these efforts could dramatically improve prospects for the development of an effective therapeutic capable of preventing and/or reversing T1D, as well as to provide novel biomarkers for disease susceptibility and autoimmune activity associated with the disease. RELEVANCE: The successful completion of these studies will be beneficial to improving our understanding of events critical to the natural history of progression to T1D; identify biomarkers capable of serving as screening tools for pathogenic and therapeutic based efforts for the disorder; and potentially, to uncover immunotherapies capable of preventing or reversing the disease. Project 1: Interferon / in Type 1 Diabetes Pathogenesis Project Leader (PL): Clare-Salzler, Michael Description (as provided by applicant): Avoidance of autoimmunity relies on carefully regulated and appropriate interplay between genetics, the environment, and components of both the innate and adaptive (acquired) immune systems; a central hypothesis to this P01. Given the innate immune system's role in monitoring the microbiologic and biochemical environments, and providing rapid protective acquired immune responses, it is well positioned to break tolerance in response to environmental signals. Dendritic cells [DC] provide this linkage, in part, through pattern recognition receptors [e.g., toll like receptors [TLR], and retinoic acid-induced gene 1-like-receptors [RLR] that detect bacterial/viral/biochemical and self molecular signatures leading to DC activation and inflammation. DC activation by TLR/RLR results in type 1 interferons [IFN/] that drive DC maturation, Th1, antibody, and CTL responses. Project 1 poses an interdigitating hypothesis; the conjoint defects in type 1 IFN biology, hyperactive IFN/ responses and increased plasmacytoid DC (PDC)/IFN/ production in the islet microenvironment play a critical role in T1D pathogenesis. These defects, investigated with Project 2, promote; a) loss of cell function, b) immunogenic DC, c) pro-inflammatory macrophages [MF], d) Th1 responses, e) enhanced CTL and cell killing and f) downgrading of protective Treg and iNKT cell responses. As a corollary, the defects reach full potential when PDC or other immune cells are activated by exogenous or endogenous factors that stimulate IFN/ production, linking environment and immunogenetics. In addition, a major emphasis will be to evaluate the effect of specific candidate genotypes, (IFIH1,Tyk2) identified in genome wide association studies (GWAS) and affecting IFN/ biology, on specific immune cell function and cell function. We believe Project 1 finds marked significance and innovation through the integrative approach afforded by the P01 mechanism (with Project 2), and quite importantly, our ability to explore lymphoid and pancreatic tissues from the nPOD program. RELEVANCE: In sum, patients with type 1 diabetes, as well as those at risk for developing the disease, would benefit from this translational research effort. In addition, Project 1 holds the promise of providing detailed mechanistic information on disease pathogenesis of human T1D, as well as novel therapeutics for preventing and/or reversing the disorder.